Resumen:
Rett
syndrome is a neurodevelopment disorder associated with intellectual
disabilities and caused by loss-of-function mutations in the transcriptional
regulator MeCP2. Hippocampal slices from symptomatic Mecp2 mutant mice
show network hyperexcitability and higher frequency of spontaneous multi-unit
spikes in the CA3 cell body layer (Calfa et al. J Neurophysiol 2011). To test
if an excitation/inhibition (E/I) imbalance is responsible for such network
hyperexcitability, we performed whole-cell recordings from CA3 pyramidal
neurons in acute slices from symptomatic Mecp2 mutant mice (P40-55) and
age-matched wildtype littermates. The amplitude of miniature excitatory
postsynaptic currents (mEPSC) was significantly larger in Mecp2 mutants
than in wildtypes, while the amplitude of miniature inhibitory postsynaptic
currents (mIPSC) was smaller in mutant neurons. On the other hand, mEPSC
frequency was lower in Mecp2 mutant cells, and mIPSC frequency was
higher in mutant cells, suggesting a homeostatic compensation to increased
excitatory input. Regarding action potential-dependent synaptic transmission,
the slope of the input/output (I/O) relationship of mossy fiber-evoked EPSCs
was larger in Mecp2 mutant neurons. Likewise, the slope of the I/O curve
of EPSCs evoked by stimulation of associational/collateral fibers was larger in
Mecp2 mutant cells. Consistent with an imbalance favoring excitation,
the I/O curve of evoked IPSCs had a smaller slope in Mecp2 mutant
neurons. Mecp2 mutant mice have a normal density of
parvalbumin-expressing interneurons in CA3, which show intrinsic membrane
properties (e.g. excitability) comparable to wildtype interneurons. Since
inhibitory and excitatory synaptic input onto CA3 interneurons seems unaffected
in Mecp2 mutant mice, the observed E/I imbalance in CA3 pyramidal
neurons may originate from impaired GABA release at the level of presynaptic
terminals. Altogether, these results demonstrate that a loss-of-function
mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal
neurons, leading to an hyperexcitable hippocampal network, likely contributing
to limbic seizures in Mecp2 mutant mice and Rett individuals.